EP2176251B1 - 5-pyridinone substituted indazoles and pharmaceutical compositions thereof - Google Patents

5-pyridinone substituted indazoles and pharmaceutical compositions thereof Download PDF

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EP2176251B1
EP2176251B1 EP08796320A EP08796320A EP2176251B1 EP 2176251 B1 EP2176251 B1 EP 2176251B1 EP 08796320 A EP08796320 A EP 08796320A EP 08796320 A EP08796320 A EP 08796320A EP 2176251 B1 EP2176251 B1 EP 2176251B1
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EP
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compound according
nmr
mhz
mmol
pyridin
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French (fr)
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EP2176251A2 (en
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Peter Guzzo
Matthew David Surman
Alan John Henderson
Mark Hadden
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Curia Global Inc
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Albany Molecular Research Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the invention relates to human melanin-concentrating hormone (MCH 1 ) receptor-selective antagonist 5-pyridinone substituted indazoles that are useful for treating obesity, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of obesity, anxiety, depression, and psychiatric disorders in a mammal.
  • MCH 1 human melanin-concentrating hormone
  • Obesity and the multitude of co-morbidities associated with obesity such as diabetes, dyslipidemia, coronary heart disease, and certain cancers are a major concern for public health.
  • the currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use.
  • MCH Melanin-concentrating hormone
  • mice lacking MCH are hypophagic and lean with increased metabolic rate, whereas animals over-expressing MCH gain excess weight on both standard and high fat diets. MCH is thought to have effects on other nervous system functions as well ( Rocksz, L. L. Biological Examination of Melanin Concentrating Hormone 1: Multi-tasking from the hypothalamus Drug News Perspect 19(5), 273, 2006 ).
  • GPCR G-protein coupled receptor
  • WO2007/029847 describes bicyclic aromatic substituted pyridone derivatives that are melanin concentrating hormone receptor antagonists.
  • WO2005/018557 discloses substituted pyridines useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity.
  • EP1741703 discloses pyridone derivatives that are melanin concentrating hormone receptor antagonists.
  • WO2008/086404 refers to 5-pyridinone substituted indazoles that are human melanin-concentrating hormone receptor antagonists.
  • a compound of formula I wherein n is 0 or 1; R is NR 1 R 2 , wherein R 1 and R 2 are each independently H and optionally substituted alkyl, or R 1 and R 2 , together with the N atom to which they are attached, form a 4-7 membered optionally substituted non-aromatic heterocyclic ring which optionally contains 1 or 2 heteroatoms in addition to the N atom shown; R 3 and R 4 are each independently H or alkyl; or R may combine with either R 3 or R 4 to form an optionally substituted pyrrolidin-2-yl; B is selected from ary, heteroaryl, and cycloalkyl; R 5 , R 6 , R 7 are each independently selected from H, -OH, -O-alkyl, alkyl, halo, -CF 3 , and -CN, -O-aryl, heteroaryl, and hetercyclyl; and R 14 is H or
  • n when n is 0, R 3 and R 4 are H and R is pyrrolidin-1-yl, then when B is a bicyclic aromatic heterocycle, either (i) at least one heteroatom of said bicyclic aromatic heterocycle is adjacent to the position where B attaches to the pyridinone moiety, or (ii) the ring of said bicyclic aromatic heterocycle which attaches to the pyridinone moiety does not contain a heteroatom.
  • R is selected from the group consisting of pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, morpholin-4-yl, 3-hydroxymethylpyrrolidin-1-yl, dimethylamino, piperazin-1-yl, amino, and 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl.
  • R is selected from S-3-hydroxypyrrolidin-1-yl, R -3-hydroxypyrrolidin-1-yl, S -3-hydroxymethylpyrrolidin-1-yl, R- 3-hydroxymethylpyrrolidin-1-yl, and (1 S ,4 S )-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl.
  • R combines with either R 3 or R 4 to form pyrrolidin-2-yl.
  • R 3 and R 4 are both H.
  • n is 0. In other embodiments, n is 1.
  • B is phenyl.
  • B, taken together with R 5 , R 6 and R 7 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 3-chlorophenyl, 3-phenoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 2-cyano-4-fluorophenyl, 2,4-dimethoxy-phenyl, 2,4-difluorophenyl, 4-isopropoxyphenyl, 2,4-di-trifluoromethylphenyl, 4- n -butoxy-2-methylphenyl, 2-methylphenyl, 4-benzyloxy-2-methylphenyl, 4-chloro-2-methoxyphenyl, benzodioxo
  • B, taken together with R 5 , R 6 and R 7 is selected from napthalen-1-yl and naphthalen-2-yl. In some embodiments of the invention, B, taken together with R 5 , R 6 and R 7 , is benzothiophene or benzofuran. In some embodiments, B, taken together with R 5 , R 6 and R 7 , is selected from benzothio-phene-2-yl and benzofuran-2-yl. In some embodiments of the invention, B is indole. In some embodiments, B is N-alkyl substituted indole.
  • B taken together with R 5 , R 6 and R 7 , is selected from 1-methylindol-2-yl, 1-methylindol-5-yl, 5-methoxyindol-2-yl, and 1-methyl-5-methoxyindol-2-yl.
  • B is pyridine.
  • B, taken together with R 5 , R 6 and R 7 is selected from 5-methylpyridine-2-yl, 5-chloropyridin-2-yl and 5-trifluoromethylpyridin-2-yl.
  • B, taken together with R 5 , R 6 and R 7 is selected from quinoline, quinazoline and optionally substituted pyridazine. In some embodiments, B, taken together with R 5 , R 6 and R 7 , is selected from quinolin-2-yl, quinazolin-2-yl, 6-trifluoromethylpyridazin-3-yl. In some embodiments, B, taken together with R 5 , R 6 and R 7 , is 1-methylindazol-5-yl. In some embodiments, B, taken together with R 5 , R 6 and R 7 , is 5-methylbenzisoxazol-2-yl.
  • B, taken together with R 5 , R 6 and R 7 is 4-methylcyclohex-1-enyl. In some embodiments, B, taken together with R 5 , R 6 and R 7 , is 4-methylcyclohex-1-yl.
  • the compound is selected from one of the following: or a pharmaceutically acceptable salt form of the foregoing.
  • the pharmaceutically acceptable salt form comprises an HCl salt.
  • the compound is selected from the group comprising: and or a pharmaceutically acceptable salt form of the foregoing.
  • the pharmaceutically acceptable salt form comprises an HCl salt.
  • the compound is selected from the group comprising: or a pharmaceutically acceptable salt form of the foregoing.
  • the pharmaceutically acceptable salt form comprises an HCl salt.
  • the compound is selected from the group comprising: and or a pharmaceutically acceptable salt form of the foregoing.
  • the pharmaceutically acceptable salt form comprises an HCl salt.
  • composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons.
  • Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and s-and t-butyl.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, and adamantyl. Other examples of cycloalkyl groups include c-propenyl, c-butenyl, c-pentenyl, and c-hexenyl.
  • Hydrocarbon e.g. C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20
  • phenylene refers to ortho, meta or para residues of the formulae:
  • Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Lower-alkoxy refers to groups containing one to four carbons.
  • alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring.
  • phenyl substituted by alkoxy may be, for example,
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy and 3,6,9-trioxadecyl.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, ⁇ 196 , but without the restriction of ⁇ 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds).
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl and benzyloxycarbonyl.
  • Lower-acyl refers to groups containing one to four carbons.
  • Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents.
  • Heteroaryl contains one, two or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings.
  • Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl and phenethyl.
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • prodrug refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine and chlorine include 3 H, 14 C, 35 S, 18 F, 32 P, 33 P, 125 I, and 36 Cl, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • the terms “methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders.
  • preventing refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition.
  • prevent is not an absolute term.
  • reference to “treatment” of a patient is intended to include prophylaxis.
  • mammal is used in its dictionary sense.
  • the term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
  • Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
  • the salt is a hydrochloride salt.
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer.
  • a compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality.
  • the removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively.
  • a comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry . The list, which is typically presented in a table entitled "Standard List of Abbreviations”.
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
  • active ingredient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders and disintegrating agents. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers and dyes. Any such optional ingredient must be compatible with the compound of formula I to insure the stability of the formulation.
  • the composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
  • additives including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and hydrates thereof, and amino acids, for example alanine
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • a dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, I to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g.
  • the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes.
  • the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g.
  • WO 97/11682 via a liposomal formulation (see, e.g., EP 736299 , WO 99/59550 and WO 97/13500 ), via formulations described in WO 03/094886 or in some other form.
  • the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods ( Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115 )).
  • the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
  • the agents can be coated on a stent.
  • the agents can be administered using high-velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336 . Additional particle formulations are described in WO 00/45792 , WO 00/53160 , and WO 02/19989 .
  • An example of a transdermal formulation containing plaster and the absorption promoter dimethylisorbide can be found in WO 89/04179 .
  • WO 96/11705 provides formulations suitable for transdermal administration.
  • the agents can be administered in the form a suppository or by other vaginal or rectal means.
  • the agents can be administered in a transmembrane formulation as described in WO 90/07923 .
  • the agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706 .
  • the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621 .
  • the agents can be administered intranasaly using the formulation described in U.S. 5,179,079 .
  • Formulations suitable for parenteral injection are described in WO 00/62759 .
  • the agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108 .
  • the agents can be administered using the particulate formulations described in U.S. 20020034536 .
  • intratracheal formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. 6,524,557 and references therein.
  • surfactants described in U.S. 6,524,557 e.g., a C 8 -C 16 fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
  • dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler.
  • Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456 .
  • WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S. 5,230,884 , U.S. 5,292,499 , WO 017/8694 , WO 01/78696 , U.S. 2003019437 , U. S. 20030165436 , and WO 96/40089 (which includes vegetable oil).
  • Sustained release formulations suitable for inhalation are described in U.S. 20010036481A1 , 20030232019A1 , and U.S. 20040018243A1 as well as in WO 01/13891 , WO 02/067902 , WO 03/072080 , and WO 03/079885 .
  • Pulmonary formulations containing microparticles are described in WO 03/015750 , U.S. 20030008013 , and WO 00/00176 .
  • Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671 .
  • Other aerosol formulations are described in EP 1338272A1 WO 90/09781 , U.
  • Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
  • Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
  • More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy .
  • Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
  • the agent can be incorporated into a liposome to improve half-life.
  • the agent can also be conjugated to polyethylene glycol (PEG) chains.
  • PEG polyethylene glycol
  • Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
  • the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108 .
  • the agents can be formulated in microcapsules as described in WO 88//01165 .
  • the agent can be administered intra-orally using the formulations described in U.S. 20020055496 , WO 00/47203 , and U.S. 6,495,120 .
  • the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2 .
  • Table 1 lists compounds representative of embodiments of the invention.
  • compounds of formula 1 may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • Compounds of formula 2 (wherein Z 1 is chlorine, bromine or iodine) can be prepared by treating compounds of formula I with NaNO 2 in acetic acid at room temperature.
  • compounds of formula 2 can be prepared by treatment of amino indazoles 3 with NaNO 2 and copper halide.
  • compounds of formula 2 can be prepared by treatment of aldehydes 4 with hydrazine under heated conditions.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and tetrahydrofuran (THF).
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N- dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • compounds of formula 8 can be treated under acidic reaction conditions to provide compounds of formula 9.
  • compounds of formula 8 can be treated with an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO to give compounds of formula 9.
  • an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO
  • Treatment of compounds 9 with amines 10 and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or picoline-borane complex can provide compounds of formula 11.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N- dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • compounds of formula 8 can be treated with diamines 14 (wherein R 10 , R 11 , R 12 are each independently H or alkyl) and trimethylaluminum to provide compounds of formula 15.
  • compounds of formula 18 can be be treated with acetic anhydride under heated conditions followed by methanol and water or methanol and sodium hydroxide under ambient to heated conditions to provide compounds of formula 19.
  • compounds of formula 21 can be heated under acid conditions to provide compounds of formula 19.
  • Compounds of formula 6 can be treated under heated conditions with a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and 4-(benzyloxy)pyridin-2(1 H )-one to give compounds of formula 23.
  • a catalyst such as copper iodide
  • a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline
  • a base such as potassium carbonate, cesium carbonate or potassium phosphate
  • 4-(benzyloxy)pyridin-2(1 H )-one to give compounds of formula 23.
  • compounds of formula 23 can be treated with hydrogen and a catalyst such as palladium on carbon to provide compounds of formula 24.
  • the hydroxyl group on compounds of formula 24 can be converted to an appropriate activating group to give compounds of formula 25.
  • compounds of formula 24 can be treated with trifluoromethylsulfonic anhydride or N -phenyl trifluoromethanesulfonamide and a base such as pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 25.
  • compounds of formula 25 (wherein Z 6 is triflate) can be be treated with hexaalkylditin and palladium(0) under heated conditions to give compounds of formula 25, wherein Z 6 is trialkylstannane.
  • compounds of formula 8 can be treated under heated conditions with a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and 4-(benzyloxy)pyridin-2(1 H )-one to give compounds of formula 27.
  • a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline
  • a base such as potassium carbonate, cesium carbonate or potassium phosphate and 4-(benzyloxy)pyridin-2(1 H )-one
  • compounds of formula 27 can be treated with an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO to give compounds of formula 28.
  • an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO
  • compounds of formula 28 Treatment of compounds 28 with amines 10 and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or picoline-borane complex can provide compounds of formula 23, which may be converted to compounds of formula 26 as described above.
  • compounds of formula 32 can be made starting from compounds of formula 29.
  • Compounds of formula 29 (wherein Z 7 is an activating group such as fluorine, chlorine, bromine or iodine) can be treated under heated conditions in a solvent such as DMF with a base such as sodium carbonate or cesium carbonate and 4-(benzyloxy)pyridin-2(1 H )-one to give a compound of formula 30.
  • compound 30 can be treated under reducing conditions such as SnCl 2 , iron powder and NH 4 Cl, or palladium on carbon under a hydrogen atmosphere to provide a compound of formula 31.
  • Treatment of compound 31 with NaNO 2 in acetic acid at room temperature can provide a compound of formula 32.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Compounds of formula 23 can be converted to compounds of formula 26 as described above.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Compounds of formula 27 can be converted to compounds of formula 26 as described above.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • compounds of formula 6 can be treated under heated conditions with a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 19 to give compounds of formula 26.
  • a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 19 to give compounds of formula 26.
  • compounds of formula 8 can be treated under heated conditions with a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 19 to give compounds of formula 34.
  • a catalyst such as copper iodide, a ligand such as trans -1,2-diaminocyclohexane or 8-hydroxyquinoline
  • a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 19 to give compounds of formula 34.
  • compounds of formula 34 can be treated with an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO to give compounds of formula 35.
  • an oxidizing agent such as the Dess-Martin periodane or oxalyl chloride and DMSO
  • compounds of formula 35 Treatment of compounds 35 with amines 10 and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or picoline-borane complex can provide compounds of formula 26.
  • compounds of formula 34 can be treated with diamines 14 (wherein R 10 , R 11 , R 12 are each independently H or alkyl) and trimethylaluminum to provide compounds of formula 36.
  • compounds of formula 39 can be made starting from compounds of formula 29.
  • Compounds of formula 29 (wherein Z 7 is an activating group such as fluorine, chlorine, bromine or iodine) can be treated under heated conditions in a solvent such as DMF with a base such as sodium carbonate and compounds of formula 19 to give compounds of formula 37.
  • compounds of formula 37 can be treated under reducing conditions such as SnCl 2 , iron powder and NH 4 Cl, or palladium on carbon under a hydrogen atmosphere to provide compounds of formula 38.
  • Treatment of compounds of formula 38 with NaNO 2 in acetic acid at room temperature can provide compounds of formula 39.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N- dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Compounds of formula 34 can be converted to compounds of formula 26 as described above.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Typical bases include but are not limited to cesium carbonate, potassium carbonate and sodium hydride.
  • Typical solvents include but are not limited to N,N -dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
  • Treatment of compounds 42 with amines 10 and a Lewis acid such as lithium perchlorate in a sovent such as tetrahyrdrofuran can provide compounds of formula 43.
  • compounds of formula 26 can be treated with hydrogen gas and a catalyst such as palladium on carbon to provide compounds of formula 44, wherein B is fully saturated cycloalkyl.
  • HPLC High performace liquid chromatograph
  • the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure.
  • the material was purified by column chromatography (silica gel, 9:1 CH 2 Cl 2 /MeOH to 90:9:1 CH 2 Cl 2 /MeOH /conc. NH 4 OH).
  • the dried residue 160 mg, 0.35 mmol
  • the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure.
  • the material was purified by column chromatography (silica gel, 9:1 CH 2 Cl 2 /MeOH to 90:9:1 CH 2 Cl 2 /MeOH /conc. NH 4 OH).
  • the dried residue (197 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.36 mL, 0.45 mmol) was added.
  • the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure.
  • the material was purified by column chromatography (silica gel, 9:1 CH 2 Cl 2 /MeOH to 90:9:1 CH 2 Cl 2 /MeOH /conc. NH 4 OH).
  • the dried residue (198 mg, 0.43 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.38 mL, 0.47 mmol) was added.
  • the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with water (25 mL), brine (25 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure.
  • the material was purified by column chromatography (silica gel, 9:1 CH 2 Cl 2 /MeOH to 90:9:1 CH 2 Cl 2 /MeOH /conc. NH 4 OH).
  • the dried residue (233 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.42 mL, 0.53 mmol) was added.
  • Cell membrane homogenates (5 ⁇ g protein) were incubated for 60 min at 22°C with 0.1 nM [ 125 I][Phe 13 ,Tyr 19 ]-MCH in the absence or presence of the test compound in a buffer containing 25 mM Hepes/Tris (pH 7.4), 5 mM MgCl 2 , I mM CaCl 2 and 0.5% bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed several times with an ice-cold buffer containing 25 mM Hepes/Tris (pH 7.4), 500 mM NaCl, 5 mM MgCl 2 , 1 mM CaCl 2 and 0.1% BSA using a 96-sample cell harvester (Unifilter, Packard).
  • the filters were dried, then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
  • the results are expressed as a percent inhibition of the control radioligand specific binding.
  • the IC 50 value concentration causing a half-maximal inhibition of control specific binding
  • Hill coefficient ( n H ) were determined by non-linear regression analysis of the competition curve using Hill equation curve fitting.
  • Nonspecific binding was determined in the presence of 50 ⁇ M 1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea. Following incubation, the samples were filtered rapidly under vacuum through Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, and washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0) using a Skatron cell harvester. The filters were counted for radioactivity in a liquid scintillation counter (Tri-Carb 2100TR, Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).
  • the results are expressed as a percent inhibition of the control radioligand specific binding.
  • the IC 50 value concentration causing a half-maximal inhibition of control specific binding
  • Hill coefficient ( n H ) were determined by non-linear regression analysis of the competition curve using Hill equation curve fitting.

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WO2009015037A3 (en) 2009-04-30
ES2382982T3 (es) 2012-06-15
JP2010534248A (ja) 2010-11-04
WO2009015037A2 (en) 2009-01-29
NZ582586A (en) 2011-12-22
AU2008279321B2 (en) 2013-08-01
EP2176251A2 (en) 2010-04-21
BRPI0814772A2 (pt) 2015-03-03
US20090082359A1 (en) 2009-03-26
US8273770B2 (en) 2012-09-25
CN101861311A (zh) 2010-10-13
HK1142608A1 (en) 2010-12-10
CA2693377A1 (en) 2009-01-29
AU2008279321A1 (en) 2009-01-29
KR20100044225A (ko) 2010-04-29

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